論文 - 詳細
| RRC ID | 76461 |
|---|---|
| 著者 | Sekiya S, Fukuda J, Yamamura R, Ooshio T, Satoh Y, Kosuge S, Sato R, Hatanaka KC, Hatanaka Y, Mitsuhashi T, Nakamura T, Matsuno Y, Hirano S, Sonoshita M. |
| タイトル | Drosophila Screening Identifies Dual Inhibition of MEK and AURKB as an Effective Therapy for Pancreatic Ductal Adenocarcinoma. |
| ジャーナル | Cancer Res |
| Abstract |
UNLABELLED:Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The '4-hit' flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC. SIGNIFICANCE:Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy. |
| ページ | OF1-OF12 |
| 公開日 | 2023-6-28 |
| DOI | 10.1158/0008-5472.CAN-22-3762 |
| PII | 727534 |
| PMID | 37378549 |
| MeSH | Animals Aurora Kinase B Carcinoma, Pancreatic Ductal* / drug therapy Carcinoma, Pancreatic Ductal* / genetics Carcinoma, Pancreatic Ductal* / pathology Drosophila Humans Mice Mitogen-Activated Protein Kinase Kinases / genetics Pancreatic Neoplasms* / drug therapy Pancreatic Neoplasms* / genetics Pancreatic Neoplasms* / pathology |
| IF | 9.727 |
| リソース情報 | |
| ヒト・動物細胞 | MIA Paca2(RCB2094) PANC-1(RCB2095) |
| ショウジョウバエ | |